2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: a case report (original) (raw)
Related papers
Molecular Genetics & Genomic Medicine, 2021
BackgroundIsobutyryl‐CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched‐chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl‐CoA dehydrogenase deficiency (IBDD), which is identified by increased C4‐acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis.MethodsHere, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature.ResultsTo assess whether a phenotype‐genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4‐acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these paramet...
Molecular Genetics and Metabolism, 2008
2-Methylbutyryl-CoA dehydrogenase (MBD; coded by the ACADSB gene) catalyzes the step in isoleucine metabolism that corresponds to the isovaleryl-CoA dehydrogenase reaction in the degradation of leucine. Deficiencies of both enzymes may be detected by expanded neonatal screening with tandem-mass spectrometry due to elevated pentanoylcarnitine (C5 acylcarnitine) in blood, but little information is available on the clinical relevance of MBD deficiency. We biochemically and genetically characterize six individuals with MBD deficiency from four families of different ethnic backgrounds. None of the six individuals showed clinical symptoms attributable to MBD deficiency although the defect in isoleucine catabolism was demonstrated both in vivo and in vitro. Several mutations in the ACADSB gene were identified, including a novel one. MBD deficiency may be a harmless metabolic variant although significant impairment of valproic acid metabolism cannot be excluded and further study is required to assess the long-term outcome of individuals with this condition. The relatively high prevalence of ACADSB gene mutations in control subjects suggests that MBD deficiency may be more common than previously thought but is not detected because of its usually benign nature.
Molecular Genetics and Metabolism, 2008
The medical and neurodevelopmental characteristics of 14 children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) are described. Eight were detected as neonates by newborn screening. Three children diagnosed on the basis of clinical symptoms had normal newborn screening results while 3 were born in states that did not screen for SCADD. Treatment included frequent feedings and a low fat diet. All children identified by newborn screening demonstrated medical and neuropsychological development within the normative range on follow-up, although one child had a relative weakness in the motor area and another child exhibited mild speech delay. Of the 3 clinically identified children with newborn screening results below the cutoff value, 2 were healthy and performed within the normal range on cognitive and motor tests at follow-up. Four clinically identified children with SCADD experienced persistent symptoms and/or developmental delay. However, in each of these cases, there were supplementary or alternative explanations for medical and neuropsychological deficits. Results indicated no genotypephenotype correlations. These findings suggest that SCADD might be benign and the clinical symptoms ascribed to SCADD reflective of ascertainment bias or that early identification and treatment prevented complications that may have occurred due to interaction between genetic susceptibility and other genetic factors or environmental stressors.
PEDIATRICS, 2003
Objective. 2-Methylbutyryl-CoA dehydrogenase deficiency, also known as short/branchedchain acyl-CoA dehydrogenase (SBCAD) deficiency, is a recently described autosomal recessive disorder of L-isoleucine metabolism. Only 4 affected individuals in 2 families have been described. One patient developed athetoid cerebral palsy, and another had severe motor developmental delay with muscle atrophy. A sibling of the first patient is asymptomatic after prenatal diagnosis and early treatment. Family investigations in the second family revealed that the patient's mother was also affected but asymptomatic.
American Journal of Human Genetics, 2000
Acyl-CoA dehydrogenase (ACAD) defects in isoleucine and valine catabolism have been proposed in clinically diverse patients with an abnormal pattern of metabolites in their urine, but they have not been proved enzymatically or genetically, and it is unknown whether one or two ACADs are involved. We investigated a patient with isolated 2-methylbutyrylglycinuria, suggestive of a defect in isoleucine catabolism. Enzyme assay of the patient's fibroblasts, using 2-methylbutyryl-CoA as substrate, confirmed the defect. Sequence analysis of candidate ACADs revealed heterozygosity for the common short-chain ACAD A625 variant allele and no mutations in ACAD-8 but a 100bp deletion in short/branched-chain ACAD (SBCAD) cDNA from the patient. Our identification of the SBCAD gene structure (11 exons; 120 kb) enabled analysis of genomic DNA. This showed that the deletion was caused by skipping of exon 10, because of homozygosity for a 1228GrA mutation in the patient. This mutation was not present in 118 control chromosomes. In vitro transcription/translation experiments and overexpression in COS cells confirmed the disease-causing nature of the mutant SBCAD protein and showed that ACAD-8 is an isobutyryl-CoA dehydrogenase and that both wild-type proteins are imported into mitochondria and form tetramers. In conclusion, we report the first mutation in the SBCAD gene, show that it results in an isolated defect in isoleucine catabolism, and indicate that ACAD-8 is a mitochondrial enzyme that functions in valine catabolism.
Scientific Reports, 2021
Autism Spectrum Disorder (ASD) and learning disabilities are neurodevelopmental disabilities characterized by dramatically increasing incidence rates, yet the exact etiology for these disabilities is not identified. Impairment in tryptophan metabolism has been suggested to participate in the pathogenesis of ASD, however, further validation of its involvement is required. Additionally, its role in learning disabilities is still uninvestigated. Our objective was to evaluate some aspects of tryptophan metabolism in ASD children (N = 45) compared to children with learning disabilities (N = 44) and healthy controls (N = 40) by measuring the expression levels of the MAOA, HAAO and AADAT genes using real-time RT-qPCR. We also aimed to correlate the expression patterns of these genes with parental ages at the time of childbirth, levels of serum iron, and vitamin D3 and zinc/copper ratio, as possible risk factors for ASD. Results demonstrated a significant decrease in the expression of the s...
2012
Background: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation with highly variable biochemical, genetic, and clinical characteristics. SCADD has been associated with accumulation of butyryl-CoA byproducts, including butyrylcarnitine (C4), butyrylglycine, ethylmalonic acid (EMA), and methylsuccinic acid (MS) in body fluid and tissues. Differences in genotype frequencies have been shown between patients diagnosed clinically versus those diagnosed by newborn screening. Moreover, while patients diagnosed clinically have a variable clinical presentation including developmental delay, ketotic hypoglycemia, epilepsy and behavioral disorders, studies suggest patients diagnosed by newborn screening are largely asymptomatic. Scant information is published about the biochemical, genetic and clinical outcome of SCADD patients diagnosed by newborn screening. Methods: We collected California newborn screening, follow-up biochemical levels, and ACADS mutation data from September, 2005 through April, 2010. We retrospectively reviewed available data on SCADD cases diagnosed by newborn screening for clinical outcomes. Results: During the study period, 2,632,058 newborns were screened and 76 confirmed SCADD cases were identified. No correlations between initial C4 value and follow-up biochemical markers (C4, EMA or MS levels) were found in the 76 cases studied. We found significant correlation between urine EMA versus MS, and correlation between follow-up C4 versus urine EMA. Of 22 cases where ACADS gene sequencing was performed: 7 had two or more deleterious mutations; 8 were compound heterozygotes for a deleterious mutation and common variant; 7 were homozygous for the common variant c.625 G > A; and 1 was heterozygous for c.625 G > A. Significant increases in mean urine EMA and MS levels were noted in patients with two or more deleterious mutations versus mutation heterozygotes or common polymorphism homozygotes. Clinical outcome data was available in 31 patients with follow-up extending from 0.5 to 60 months. None developed epilepsy or behavioral disorders, and three patients had isolated speech delay. Hypoglycemia occurred in two patients, both in the neonatal period. The first patient had concomitant meconium aspiration; the other presented with central apnea, poor feeding, and hypotonia. The latter, a c.625 G > A homozygote, has had persistent elevations in both short-and medium-chain acylcarnitines; diagnostic workup in this case is extensive and ongoing. Conclusions: This study examines the largest series to date of SCADD patients identified by newborn screening. Our results suggest that confirmatory tests may be useful to differentiate patients with common variants from those with deleterious mutations. This study also provides evidence to suggest that, even when associated with deleterious mutations, SCADD diagnosed by newborn screening presents largely as a benign condition.
Turkish Journal of Pediatrics, 2019
Guanidinoacetate methyltransferase (GAMT) deficiency is a rare autosomal recessive disorder of creatine biosynthesis. Here, we report 9 and 10-year-old cousins with GAMT deficiency caused by a novel mutation who both exhibited neurodevelopmental retardation, seizures, behavioral problems, and autism that began during early infancy. The patients were diagnosed as having only autism and followed for years without a specific diagnosis although they had very low levels of serum creatinine for several times. A novel nonsense mutation in the GAMT gene that caused cessation of synthesis of the protein encoded by this gene was identified in these patients. GAMT deficiency is a treatable inborn error of metabolism and should be considered for all patients with hypotonia, developmental delay, seizures and autism, particularly if low serum creatinine levels are observed.
Some Biochemical Implications in Autism Spectrum Disorder
Brazilian Journal of Medicine and Human Health, 2014
Autism spectrum disorder (ASD) affects 0.6 to 1% of the population worldwide. It is characterized by a deficit in communication and social interaction, and is associated with restricted and repetitive behavior patterns. Stereotypes include inflexible adhesion to specific non-functional routines and rituals and a persistent concern with parts of objects rather than the object as a whole. Up to the present time, there are no specific tests that permit a laboratory diagnosis of the disorder to be carried out, and the syndrome is confirmed by clinical observation in the first 36 months of the patient's life. Clinical manifestations such as epilepsy, mental retardation, sleep disorders, hyperactivity, irritability and auto-and heteroaggressiveness may alter the patient's prognosis. Around 50% of children with ASD fulfill the criteria for attention deficit hyperactivity disorder (ADHD). Symptoms of oppositional defiant disorder (ODD) associated with autism appear to indicate a distinct phenotype requiring specific therapeutic measures. ASD is not a discrete nosological entity but, rather, a multifactorial syndrome associated with different phenotypic and biological presentations. Various disorders such as pathologies of the gastrointestinal tract have been linked to ASD, not only insofar as causality is concerned but also with respect to their role in aggravating the disease. Other associated disorders include lesions in physiological processes such as the redox metabolism, mitochondrial dysfunction and enzymatic regulation of essential metabolites. Currently, studies on direct and indirect markers of mitochondrial metabolism associated with anomalies found in the brain of these patients point to the possibility of these markers being used as tools with which to reach a diagnosis that would be laboratory-based rather than merely clinical.